Differential and synergistic effect of nerve growth factor and cAMP on the regulation of early response genes during neuronal differentiation.

Neurotrophin (NT)-driven differentiation is a process involving activation of multiple signalling events. Treatment of PC12 cells with the prototypic NT nerve growth factor (NGF) induces PC12 cell differentiation characterized by neurite outgrowth and expression of differentiation genes. Cyclic AMP (cAMP), one of the second messengers of NGF stimulation, has also been observed to induce neuronal differentiation in PC12 cells. Interestingly, co-treatment of NGF and dibutyryl cAMP (DBcAMP) exhibits a synergistic effect on neurite outgrowth in PC12 cells, but the mechanisms underlying this synergism remain unknown. In the current study, we compared the gene expression profiles of PC12 cells treated with NGF, DBcAMP or both for 12 h to identify differentially regulated genes during the early stage of differentiation. We found that the genes that were differentially regulated by NGF, DBcAMP or both include genes for acquiring neuronal phenotypes, cytoskeleton-binding proteins and cell cycle proteins. Importantly, we identified a subset of genes that was specifically regulated during co-treatment of NGF and cAMP, suggesting that the synergistic effect of NGF and DBcAMP on neurite outgrowth is possibly mediated through transcription regulation. Our observations provide novel insights on the signalling mechanisms underlying the regulation of neuronal differentiation by NGF and cAMP.